Ero1-Mediated Reoxidation of Protein Disulfide Isomerase Accelerates the Folding of Cone Snail Toxins.
Ero1-Mediated Reoxidation of Protein Disulfide Isomerase Accelerates the Folding of Cone Snail Toxins.
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DOI：
10.3390/ijms19113418
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发表时间：
2018-10-31
影响因子：
5.6
通讯作者：
Safavi-Hemami H
中科院分区：
文献类型：
--
作者：
O'Brien H;Kanemura S;Okumura M;Baskin RP;Bandyopadhyay PK;Olivera BM;Ellgaard L;Inaba K;Safavi-Hemami H
富含二硫键的多肽在自然界中非常丰富，它们的研究为蛋白质的折叠、结构和功能提供了迷人的见解。有毒的锥形蜗牛属于一组表达自然界中发现的最大的富含二硫化物的肽（芋螺毒素）的生物体。芋螺毒素结构支架的多样性表明，专门的分子适应性已经发展，以确保其有效的折叠和分泌。我们最近发现，典型的蛋白质二硫键异构酶（PDI）和芋螺毒素特异性的PDI（csPDI）是无处不在的表达在锥螺的毒腺，并发挥了重要作用，芋螺毒素折叠。在这里，我们确定锥螺内质网氧化还原蛋白-1（Ero 1），并通过锥螺PDI和csPDI的再氧化研究其在芋螺毒素氧化折叠中的作用。我们发现，芋螺Ero 1优先再氧化的PDI超过csPDI，这表明csPDI的再氧化可能依赖于Ero 1独立的分子途径。尽管PDI优先于csPDI再氧化，但Ero 1和csPDI的组合效应提供了比Ero 1和PDI更高的折叠产率。我们进一步证明，两个模型芋螺毒素的体外折叠率最高时，所有三种酶都存在，这表明这些酶可以协同作用。我们的研究结果提供了新的见解，最多样化的富含二硫键的肽类之一的产生，并可能改善目前的体外方法生产的毒液肽的药理学研究。
Disulfide-rich peptides are highly abundant in nature and their study has provided fascinating insight into protein folding, structure and function. Venomous cone snails belong to a group of organisms that express one of the largest sets of disulfide-rich peptides (conotoxins) found in nature. The diversity of structural scaffolds found for conotoxins suggests that specialized molecular adaptations have evolved to ensure their efficient folding and secretion. We recently showed that canonical protein disulfide isomerase (PDI) and a conotoxin-specific PDI (csPDI) are ubiquitously expressed in the venom gland of cone snails and play a major role in conotoxin folding. Here, we identify cone snail endoplasmic reticulum oxidoreductin-1 (Conus Ero1) and investigate its role in the oxidative folding of conotoxins through reoxidation of cone snail PDI and csPDI. We show that Conus Ero1 preferentially reoxidizes PDI over csPDI, suggesting that the reoxidation of csPDI may rely on an Ero1-independent molecular pathway. Despite the preferential reoxidation of PDI over csPDI, the combinatorial effect of Ero1 and csPDI provides higher folding yields than Ero1 and PDI. We further demonstrate that the highest in vitro folding rates of two model conotoxins are achieved when all three enzymes are present, indicating that these enzymes may act synergistically. Our findings provide new insight into the generation of one of the most diverse classes of disulfide-rich peptides and may improve current in vitro approaches for the production of venom peptides for pharmacological studies.
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影响因子：
4.8
作者：
Masui, Shoji;Vavassori, Stefano;Inaba, Kenji
通讯作者：
Inaba, Kenji
DOI：
10.1073/pnas.0506448103
发表时间：
2006-01-10
影响因子：
11.1
作者：
Gross, E;Sevier, CS;Fass, D
通讯作者：
Fass, D
影响因子：
4.4
作者：
Safavi-Hemami, Helena;Siero, William A.;Purcell, Anthony W.
通讯作者：
Purcell, Anthony W.
影响因子：
16
作者：
Frand, AR;Kaiser, CA
通讯作者：
Kaiser, CA
影响因子：
16
作者：
Pollard, MG;Travers, KJ;Weissman, JS
通讯作者：
Weissman, JS